Combination of the Angiogenesis Inhibitor Lucitanib with ...
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0 10 20 30 40 50 60 0 1000 2000 3000 Lucitanib MC38 Days after initial dose Tumor volume mean ± SEM (mm 3 ) Vehicle Lucitanib 10 mg/kg QD; PO Anti-PD-1 10 mg/kg BIW; IP Lucitanib + anti-PD-1 0 10 20 30 40 50 60 0 1000 2000 3000 Anti-VEGFR2 MC38 Days after initial dose Tumor volume mean ± SEM (mm 3 ) Anti-VEGFR2 40 mg/kg Q2D; IP Anti-VEGFR2 + anti-PD-1 Dosing period 0 10 20 30 40 50 0 500 1000 1500 Lucitanib H22 Days after initial dose Tumor volume mean ± SEM (mm 3 ) Vehicle Lucitanib 10 mg/kg QD; PO Anti-PD-1 5 mg/kg BIW; IP Lucitanib + anti-PD-1 0 10 20 30 40 50 0 500 1000 1500 Lenvatinib H22 Days after initial dose Tumor volume mean ± SEM (mm 3 ) Dosing period Lenvatinib + anti-PD-1 Lenvatinib 10 mg/kg QD; PO Vehicle Lucitanib Anti-PD-1 Lucitanib + anti-PD-1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 0 50 100 150 Normalized counts (median ± SD) ** ** * Rachel L. Dusek, Liliane Robillard, Thomas C. Harding, Andrew D. Simmons, Minh Nguyen Clovis Oncology, Inc., Boulder, CO Combination of the Angiogenesis Inhibitor Lucitanib with Immune Checkpoint Blockade Augments Antitumor Activity in Syngeneic Models ACKNOWLEDGMENTS These studies were funded by Clovis Oncology, Inc. Medical writing and editorial support were funded by Clovis Oncology and provided by Nathan Yardley and Frederique H. Evans of Ashfield Healthcare Communications. SITC Annual Meeting | November 6-10, 2019 | National Harbor, MD Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission from the authors. Corresponding author: Rachel L. Dusek; email: [email protected]. CONCLUSIONS • Lucitanib enhances the antitumor activity resulting from immune checkpoint blockade of either the CTLA-4 or PD-1 pathways in syngeneic nonclinical models • Lucitanib in combination with anti-PD-1 shows comparable or better antitumor activity than other angiogenesis inhibitors combined with anti-PD-1 in nonclinical studies • Lucitanib combined with anti-PD-1 promotes intratumoral T-cell infiltration and immune- associated gene expression changes important for antitumor immunity • Lucitanib’s antitumor mechanism of action involves both inhibiting angiogenesis and modulating immune effector activity, potentially through CD8+ T cells • These data provide preclinical support for clinical studies evaluating lucitanib in combination with immune checkpoint inhibitors • The combination of lucitanib and nivolumab is currently being evaluated as a treatment for patients with solid tumors (NCT04042116) Lucitanib Enhances the Antitumor Activity of Anti-PD-1 in Several Syngeneic Models INTRODUCTION Increase in Combination Efficacy No Increase in Combination Efficacy Model H22 MC38 CT26 P-BR5VFB1- Akt LLC1 EMT6 RENCA 4T1 B16F10 Cancer type Liver Colon Colon Ovarian Lung Breast Renal Breast Melanoma Efficacy (%) TGI anti-PD-1 53 64 43 19 6 5 0.6 0 –4 TGI lucitanib 62 80 76 79 40 72 85 60 77 TGI lucitanib + anti-PD-1 86 97 84 85 47 68 90 55 81 P value combination vs best monotherapy < 0.01 < 0.0001 < 0.05 < 0.05 NS NS NS NS NS Survival (days) MST vehicle 22 19.5 14 29 16 16 21 20 14 MST anti-PD-1 46.5 29 19 43 16 17.5 19 19 14 MST lucitanib 35 39 32 30.5 21 30 42 29.5 25 MST lucitanib + anti-PD-1 NR (> 63) 45 40 55 21 31.5 43.5 31 26 P value combination vs best monotherapy < 0.01 < 0.0001 < 0.01 < 0.001 NS NS NS NS NS • Lucitanib (E-3810) is an oral multikinase inhibitor with targets that are associated with angiogenesis and other key cancer and immune pathways 1 • Angiogenesis plays a critical role in cancer growth and metastasis through tumor vascularization and also promotes immunosuppression within the tumor microenvironment 2,3 REFERENCES 1. Bello et al. Cancer Res. 2011;71:1396-405. 2. Fukumura et al. Nat Rev Clin Oncol. 2018;15:325-40. 3. Khan et al. Nat Rev Clin Oncol. 2018;15:310-24. 4. McDermott et al. Nat Med. 2018;24:749-57. 5. Rini et al. N Engl J Med. 2019;380:1116-27. 6. Allen et al. Sci Transl Med. 2017;9(385):eaak9679. 7. Kato et al. PLoS One. 2019;14(2):e0212513. 8. Kimura et al. Cancer Sci. 2018;109(12):3993-4002. 9. Makker et al. The Lancet. 2019;20(5):711-18. 10. Lee et al. J Clin Oncol. 2018;36(15 suppl):abstr 4560. 11. Hodi et al. Cancer Immunol Res. 2014; 2:632-42. • Therapies simultaneously targeting angiogenesis and immune checkpoint pathways may enhance antitumor responses by modulating the tumor microenvironment 2,3 – For example, inhibiting VEGF signaling is thought to induce vascular normalization, increase intratumoral T-cell infiltration, promote dendritic cell maturation, modulate the expression of cell adhesion molecules, and alter immune cell populations, whereas interfering with immune checkpoint pathways can enhance T-cell activation, expansion, and effector responses Lucitanib Augments the Antitumor Activity of Anti-CTLA-4 in the MC38 Syngeneic Mouse Model Antitumor Activity of Lucitanib Combined with Anti-PD-1 Is Similar to or Better Than That of Other Angiogenesis Inhibitor Anti-PD-1 Combinations • Combination therapies targeting angiogenesis and immune checkpoint pathways have demonstrated favorable activity in preclinical and clinical studies. 4-8 For example, – The combination of lenvatinib and pembrolizumab has shown encouraging activity in patients with renal cell and endometrial carcinomas 9,10 – The combination of bevacizumab and ipilimumab has shown promising activity in patients with melanoma 11 • We hypothesize that the combination of lucitanib with an immune checkpoint inhibitor may also demonstrate beneficial preclinical and clinical activity • Preclinical studies were performed to investigate the antitumor activity and the mechanism of action of lucitanib in combination with immune checkpoint blockade in syngeneic mouse tumor models RESULTS Lucitanib Treatment Alone and in Combination with Anti-PD-1 Results in Immune-Related Gene Expression Changes MC38 Syngeneic Colon Cancer Efficacy Day 17: TGI (%) Anti-CTLA-4 57 Lucitanib 82 Lucitanib + anti-CTLA-4 91 P value lucitanib vs lucitanib + anti-CTLA-4 < 0.01 Survival: MST (days) Vehicle 18 Anti-CTLA-4 25 Lucitanib 45 Lucitanib + anti-CTLA-4 NR (> 52) P value lucitanib vs lucitanib + anti-CTLA-4 < 0.0001 Vehicle Lucitanib Anti-PD-1 Lucitanib + anti-PD-1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 -10 -5 0 5 10 T-cell Function Pathway signature score median ±SD ** ** ** * Single-agent treatments of lucitanib and anti-CTLA-4 (clone 9D9), and the combination of the two agents were evaluated in the MC38 mouse syngeneic colon cancer model (n=10 mice/group). Treatment was initiated when tumors were ≈50 mm 3 and continued for 35 days. A graph of mean tumor volume over time and the Kaplan-Meier survival curves are shown (left). Efficacy and survival data are shown in the table (right). The statistical analysis between groups was performed using a two-way ANOVA (efficacy) or log-rank (survival) test. ANOVA, analysis of variance; BIW, biweekly; IP, intraperitoneally; MST, median survival time; NR, not reached; PO, orally; QD, once daily; SEM, standard error of the mean; TGI, tumor growth inhibition Tumor samples (n=5/group) from MC38 tumor-bearing mice were harvested following seven days of treatment with lucitanib (10 mg/kg, QD; PO), anti-PD-1 (10 mg/kg BIW; IP), anti-VEGFR2 (40 mg/kg, Q2D; IP), lucitanib + anti-PD-1, or anti-VEGFR2 + anti-PD-1, and gene expression was analyzed using the Nanostring Pan Cancer Immune panel. The heatmap (left) shows relative global significance scores for the top 20 molecular pathways affected by treatment. Specific pathway signature scores are shown plotted by treatment (right). Statistical significance was determined using one-way ANOVA. ***, p < 0.001; **, p < 0.01; *, p < 0.05. CD, cluster of differentiation; NK, natural killer; SD, standard deviation. Vehicle Lucitanib Anti-PD-1 Lucitanib + anti-PD-1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 -10 -5 0 5 10 Adaptive Immunity Pathway signature score median ±SD * * * ** Lucitanib Treatment Alone and in Combination with Anti-PD-1 Increases the Abundance of Intratumoral CD8+ T Cells Tumor samples (n=5/group) from MC38 tumor bearing mice were harvested following seven days of treatment with lucitanib (10 mg/kg, QD; PO), anti-PD-1 (10 mg/kg, BIW; IP), anti-VEGFR2 (40 mg/kg, IP; Q2D), lucitanib + anti-PD-1, or anti-VEGFR2 + anti-PD-1. Intratumoral CD8-positive T-cell abundance was assessed by IHC. The IHC Profiler algorithm was used to determine the average CD8-positive area/tumor using five representative fields; the average CD8-positive tumor area per group was quantified (top left). Representative images are shown (right). To confirm these findings, RNA was isolated from the same tumors and CD8 gene expression was assessed by Nanostring (bottom left). Statistical significance was determined using one-way ANOVA. **, p < 0.01; *, p < 0.05. IHC, immunohistochemistry Proposed Mechanism of Action Vehicle Lucitanib Anti-PD-1 Lucitanib + anti-PD-1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 -10 -5 0 5 10 Innate Immunity Pathway signature score median ±SD *** ** * ** Vehicle Lucitanib Anti PD-1 Lucitanib + anti PD-1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 -10 -5 0 5 10 Cytokines and Receptors Pathway signature score median ±SD ** * * ** Single-agent treatments of lucitanib and anti-PD-1 (clone RMP1-14), and the combination of the two agents were evaluated in nine syngeneic mouse cancer models (n=10 mice/group). Treatment was initiated when tumors were ≈50-115 mm 3 and continued for up to 38 days. A graph of mean tumor volume over time and the Kaplan-Meier survival curves are shown for the CT26 colon cancer model as an example (top). Efficacy and survival data across models are shown in the table (bottom). The statistical analysis between groups was performed using a two-way ANOVA (efficacy) or log-rank (survival) test. NS, Not significant Single-agent treatments of lucitanib, anti-PD-1, anti-VEGFR2 (clone DC101), and lenvatinib, and combinations of lucitanib + anti- PD-1, anti-VEGFR2 + anti-PD-1, or lenvatinib + anti-PD-1 were evaluated in MC38 or H22 syngeneic tumor bearing mice. Treatment was initiated when tumors reached ≈50 mm 3 and continued for 28 days. Mean tumor volume over time graphs are shown (left). Treatment efficacy comparisons (TGI [%]) and statistics determined using a two-way ANOVA are shown in the table (right). Q2D, every two days 0 10 20 30 40 50 0 1000 2000 3000 Tumor Volume Days after initial dose Tumor volume mean ± SEM (mm 3 ) Lucitanib Compared to Anti-VEGFR2 0 10 20 30 40 50 60 0 20 40 60 80 100 Survival Days after initial dose Percent survival Vehicle Lucitanib 10 mg/kg QD; PO Anti-PD-1 10 mg/kg BIW; IP Lucitanib + anti-PD-1 Dosing period Lucitanib Compared to Lenvatinib CD8+ T Cells Contribute to the Antitumor Activity of Lucitanib Monotherapy 0 10 20 30 40 0 1000 2000 3000 Lucitanib Days after initial dose Tumor volume mean ± SEM (mm 3 ) Vehicle + isotype control 200 µg/mouse Q3D; IP Vehicle + anti-mCD8a 200 µg/mouse Q3D; IP Lucitanib 10 mg/kg QD; PO + isotype control 200 µg/mouse Q3D; IP Lucitanib 10 mg/kg QD; PO + anti-mCD8a 200 µg/mouse Q3D; IP 0 10 20 30 40 0 1000 2000 3000 Anti-PD-1 Days after initial dose Tumor volume mean ± SEM (mm 3 ) Anti-PD-1 10 mg/kg BIW; IP + isotype control 200 µg/mouse Q3D; IP Anti-PD-1 10 mg/kg BIW; IP + anti-mCD8a 200 µg/mouse Q3D; IP Dosing period MC38 Syngeneic Colon Cancer Group Efficacy Day 17: TGI (%) Survival: MST (days) Vehicle + isotype control – 19 Vehicle + anti-mCD8a –50 17 Lucitanib + isotype control 78 56 Lucitanib + anti-mCD8a 60 37.5 Anti-PD-1 + isotype control 56 31 Anti-PD-1 + anti-mCD8a –68 17 P value lucitanib + isotype control vs lucitanib + anti-mCD8 < 0.01 < 0.0001 MC38 tumor bearing mice were treated with lucitanib or anti-PD-1, in combination with either an isotype control (rat IgG2b clone LTF-2) or an anti-mCD8a antibody (clone 2.43). Mean tumor volumes over time are graphed (top). The Kaplan-Meier survival analysis is shown (bottom left). Efficacy and survival statistics are shown in the table (bottom right). P-values were determined using the two-way ANOVA (efficacy) or log-rank (survival) test. Q3D, every three days Vehicle Lucitanib Anti-PD-1 Lucitanib + anti-PD-1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 0.0 0.5 1.0 1.5 2.0 Average CD8 positivity (% tumor area) * CD8 Nanostring CD8 IHC Orthogonal Assay CT26 Syngeneic Colon Cancer MC38 Syngeneic Colon Cancer Efficacy (Day 19) Group TGI (%) P value vs Lucitanib + Anti-PD-1 Anti-PD-1 56 < 0.001 Lucitanib 88 < 0.01 Anti-VEGFR2 47 < 0.0001 Lucitanib + anti-PD-1 98 – Anti-VEGFR2 + anti-PD-1 63 < 0.001 H22 Syngeneic Liver Cancer Efficacy (Day 16) Group TGI (%) P value vs Lucitanib + Anti-PD-1 Anti-PD-1 53 NS Lucitanib 62 NS Lenvatinib 50 < 0.001 Lucitanib + anti-PD-1 86 – Lenvatinib + anti-PD-1 86 NS Vehicle Lucitanib Lucitanib + anti-PD1 Anti-VEGFR2 Anti-VEGFR2 + anti-PD-1 Anti-PD-1 0 10 20 30 40 50 0 1000 2000 3000 Tumor Volume Days after initial dose Tumor volume Mean ± SEM (mm 3 ) Vehicle Lucitanib 10 mg/kg QD; PO Anti-CTLA-4 10 mg/kg BIW; IP Lucitanib + anti-CTLA-4 Dosing period 0 10 20 30 40 50 0 20 40 60 80 100 Survival Days after initial dose Percent survival 0 10 20 30 40 50 60 0 20 40 60 80 100 Survival Days after initial dose Percent survival
Transcript of Combination of the Angiogenesis Inhibitor Lucitanib with ...
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Rachel L. Dusek, Liliane Robillard, Thomas C. Harding, Andrew D. Simmons, Minh NguyenClovis Oncology, Inc., Boulder, CO
Combination of the Angiogenesis Inhibitor Lucitanib with Immune Checkpoint BlockadeAugments Antitumor Activity in Syngeneic Models
ACKNOWLEDGMENTSThese studies were funded by Clovis Oncology, Inc. Medical writing and editorial support were funded by Clovis Oncology and provided by Nathan Yardley and Frederique H. Evans of Ashfield Healthcare Communications.
SITC Annual Meeting | November 6-10, 2019 | National Harbor, MDCopies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission from the authors.Corresponding author: Rachel L. Dusek; email: [email protected].
CONCLUSIONS• Lucitanib enhances the antitumor activity resulting from immune checkpoint blockade of
either the CTLA-4 or PD-1 pathways in syngeneic nonclinical models• Lucitanib in combination with anti-PD-1 shows comparable or better antitumor activity than
other angiogenesis inhibitors combined with anti-PD-1 in nonclinical studies• Lucitanib combined with anti-PD-1 promotes intratumoral T-cell infiltration and immune-
associated gene expression changes important for antitumor immunity• Lucitanib’s antitumor mechanism of action involves both inhibiting angiogenesis and
modulating immune effector activity, potentially through CD8+ T cells • These data provide preclinical support for clinical studies evaluating lucitanib in combination
with immune checkpoint inhibitors• The combination of lucitanib and nivolumab is currently being evaluated as a treatment for
patients with solid tumors (NCT04042116)
Lucitanib Enhances the Antitumor Activity of Anti-PD-1 in Several Syngeneic Models
INTRODUCTION
Increase in Combination Efficacy No Increase in Combination Efficacy
Model H22 MC38 CT26P-BR5VFB1-
AktLLC1 EMT6 RENCA 4T1 B16F10
Cancer type Liver Colon Colon Ovarian Lung Breast Renal Breast MelanomaEfficacy (%)TGI anti-PD-1 53 64 43 19 6 5 0.6 0 –4TGI lucitanib 62 80 76 79 40 72 85 60 77TGI lucitanib + anti-PD-1 86 97 84 85 47 68 90 55 81P value combination vs best monotherapy < 0.01 < 0.0001 < 0.05 < 0.05 NS NS NS NS NSSurvival (days)MST vehicle 22 19.5 14 29 16 16 21 20 14MST anti-PD-1 46.5 29 19 43 16 17.5 19 19 14MST lucitanib 35 39 32 30.5 21 30 42 29.5 25MST lucitanib + anti-PD-1 NR (> 63) 45 40 55 21 31.5 43.5 31 26P value combination vs best monotherapy < 0.01 < 0.0001 < 0.01 < 0.001 NS NS NS NS NS
• Lucitanib (E-3810) is an oral multikinase inhibitor with targets that are associated with angiogenesis and other key cancer and immune pathways1
• Angiogenesis plays a critical role in cancer growth and metastasis through tumor vascularization and also promotes immunosuppression within the tumor microenvironment2,3
REFERENCES1. Bello et al. Cancer Res. 2011;71:1396-405.2. Fukumura et al. Nat Rev Clin Oncol. 2018;15:325-40.3. Khan et al. Nat Rev Clin Oncol. 2018;15:310-24.4. McDermott et al. Nat Med. 2018;24:749-57.5. Rini et al. N Engl J Med. 2019;380:1116-27.6. Allen et al. Sci Transl Med. 2017;9(385):eaak9679.
7. Kato et al. PLoS One. 2019;14(2):e0212513.8. Kimura et al. Cancer Sci. 2018;109(12):3993-4002.9. Makker et al. The Lancet. 2019;20(5):711-18.10. Lee et al. J Clin Oncol. 2018;36(15 suppl):abstr 4560.11. Hodi et al. Cancer Immunol Res. 2014; 2:632-42.
• Therapies simultaneously targeting angiogenesis and immune checkpoint pathways may enhance antitumor responses by modulating the tumor microenvironment2,3
– For example, inhibiting VEGF signaling is thought to induce vascular normalization, increase intratumoral T-cell infiltration, promote dendritic cell maturation, modulate the expression of cell adhesion molecules, and alter immune cell populations, whereas interfering with immune checkpoint pathways can enhance T-cell activation, expansion, and effector responses
Lucitanib Augments the Antitumor Activity of Anti-CTLA-4 in the MC38 Syngeneic Mouse Model
Antitumor Activity of Lucitanib Combined with Anti-PD-1 Is Similar to or Better Than That of Other Angiogenesis Inhibitor Anti-PD-1 Combinations
• Combination therapies targeting angiogenesis and immune checkpoint pathways have demonstrated favorable activity in preclinical and clinical studies.4-8 For example, – The combination of lenvatinib and pembrolizumab has shown encouraging activity in patients with
renal cell and endometrial carcinomas9,10
– The combination of bevacizumab and ipilimumab has shown promising activity in patients with melanoma11
• We hypothesize that the combination of lucitanib with an immune checkpoint inhibitor may also demonstrate beneficial preclinical and clinical activity
• Preclinical studies were performed to investigate the antitumor activity and the mechanism of action of lucitanib in combination with immune checkpoint blockade in syngeneic mouse tumor models
RESULTS
Lucitanib Treatment Alone and in Combination with Anti-PD-1 Results in Immune-Related Gene Expression Changes
MC38 Syngeneic Colon Cancer
Efficacy Day 17: TGI (%)Anti-CTLA-4 57Lucitanib 82Lucitanib + anti-CTLA-4 91P value lucitanib vs lucitanib + anti-CTLA-4 < 0.01
Survival: MST (days)Vehicle 18Anti-CTLA-4 25Lucitanib 45Lucitanib + anti-CTLA-4 NR (> 52)P value lucitanib vs lucitanib + anti-CTLA-4 < 0.0001
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T-cell Function
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** ** **
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Single-agent treatments of lucitanib and anti-CTLA-4 (clone 9D9), and the combination of the two agents were evaluated in the MC38 mouse syngeneic colon cancer model (n=10 mice/group). Treatment was initiated when tumors were ≈50 mm3 and continued for 35 days. A graph of mean tumor volume over time and the Kaplan-Meier survival curves are shown (left). Efficacy and survival data are shown in the table (right). The statistical analysis between groups was performed using a two-way ANOVA (efficacy) or log-rank (survival) test. ANOVA, analysis of variance; BIW, biweekly; IP, intraperitoneally; MST, median survival time; NR, not reached; PO, orally; QD, once daily; SEM, standard error of the mean; TGI, tumor growth inhibition
Tumor samples (n=5/group) from MC38 tumor-bearing mice were harvested following seven days of treatment with lucitanib(10 mg/kg, QD; PO), anti-PD-1 (10 mg/kg BIW; IP), anti-VEGFR2 (40 mg/kg, Q2D; IP), lucitanib + anti-PD-1, or anti-VEGFR2 + anti-PD-1, and gene expression was analyzed using the Nanostring Pan Cancer Immune panel. The heatmap (left) shows relative global significance scores for the top 20 molecular pathways affected by treatment. Specific pathway signature scores are shown plotted by treatment (right). Statistical significance was determined using one-way ANOVA. ***, p < 0.001; **, p < 0.01; *, p < 0.05.CD, cluster of differentiation; NK, natural killer; SD, standard deviation.
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Lucitanib Treatment Alone and in Combination with Anti-PD-1 Increases the Abundance of Intratumoral CD8+ T Cells
Tumor samples (n=5/group) from MC38 tumor bearing mice were harvested following seven days of treatment with lucitanib(10 mg/kg, QD; PO), anti-PD-1 (10 mg/kg, BIW; IP), anti-VEGFR2 (40 mg/kg, IP; Q2D), lucitanib + anti-PD-1, or anti-VEGFR2 + anti-PD-1. Intratumoral CD8-positive T-cell abundance was assessed by IHC. The IHC Profiler algorithm was used to determine the average CD8-positive area/tumor using five representative fields; the average CD8-positive tumor area per group was quantified (top left). Representative images are shown (right). To confirm these findings, RNA was isolated from the same tumorsand CD8 gene expression was assessed by Nanostring (bottom left). Statistical significance was determined using one-way ANOVA. **, p < 0.01; *, p < 0.05. IHC, immunohistochemistry
Proposed Mechanism of Action
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Single-agent treatments of lucitanib and anti-PD-1 (clone RMP1-14), and the combination of the two agents were evaluated in ninesyngeneic mouse cancer models (n=10 mice/group). Treatment was initiated when tumors were ≈50-115 mm3 and continued for up to 38 days. A graph of mean tumor volume over time and the Kaplan-Meier survival curves are shown for the CT26 colon cancer model as an example (top). Efficacy and survival data across models are shown in the table (bottom). The statistical analysis between groups was performed using a two-way ANOVA (efficacy) or log-rank (survival) test. NS, Not significant
Single-agent treatments of lucitanib, anti-PD-1, anti-VEGFR2 (clone DC101), and lenvatinib, and combinations of lucitanib + anti-PD-1, anti-VEGFR2 + anti-PD-1, or lenvatinib + anti-PD-1 were evaluated in MC38 or H22 syngeneic tumor bearing mice. Treatment was initiated when tumors reached ≈50 mm3 and continued for 28 days. Mean tumor volume over time graphs are shown (left). Treatment efficacy comparisons (TGI [%]) and statistics determined using a two-way ANOVA are shown in the table (right).Q2D, every two days
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Lucitanib Compared to Lenvatinib
CD8+ T Cells Contribute to the Antitumor Activity of Lucitanib Monotherapy
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MC38 Syngeneic Colon Cancer
GroupEfficacy Day 17:
TGI (%)Survival:
MST (days)Vehicle + isotype control – 19Vehicle + anti-mCD8a –50 17
Lucitanib + isotype control 78 56Lucitanib + anti-mCD8a 60 37.5
Anti-PD-1 + isotype control 56 31Anti-PD-1 + anti-mCD8a –68 17
P value lucitanib + isotype control vs lucitanib + anti-mCD8 < 0.01 < 0.0001
MC38 tumor bearing mice were treated with lucitanib or anti-PD-1, in combination with either an isotype control (rat IgG2b cloneLTF-2) or an anti-mCD8a antibody (clone 2.43). Mean tumor volumes over time are graphed (top). The Kaplan-Meier survival analysis is shown (bottom left). Efficacy and survival statistics are shown in the table (bottom right). P-values were determined using the two-way ANOVA (efficacy) or log-rank (survival) test. Q3D, every three days
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CT26 Syngeneic Colon Cancer
MC38 Syngeneic Colon Cancer Efficacy (Day 19)
GroupTGI (%)
P value vs Lucitanib + Anti-PD-1
Anti-PD-1 56 < 0.001Lucitanib 88 < 0.01Anti-VEGFR2 47 < 0.0001Lucitanib + anti-PD-1 98 –Anti-VEGFR2 + anti-PD-1 63 < 0.001
H22 Syngeneic Liver CancerEfficacy (Day 16)
GroupTGI (%)
P value vs Lucitanib + Anti-PD-1
Anti-PD-1 53 NSLucitanib 62 NSLenvatinib 50 < 0.001Lucitanib + anti-PD-1 86 –Lenvatinib + anti-PD-1 86 NS
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0 10 20 30 40 500
1000
2000
3000
Tumor Volume
Days after initial dose
Tum
or v
olum
eM
ean±
SEM
(mm
3 )
VehicleLucitanib 10 mg/kg QD; POAnti-CTLA-4 10 mg/kg BIW; IP
Lucitanib + anti-CTLA-4Dosing period
0 10 20 30 40 500
20
40
60
80
100
Survival
Days after initial dose
Perc
ent s
urvi
val
0 10 20 30 40 50 600
20
40
60
80
100
Survival
Days after initial dose
Perc
ent s
urvi
val
